NMNAT1 – Cone-Rod Dystrophy

NMNAT1 encodes the nuclear nicotinamide mononucleotide adenylyltransferase 1 essential for NAD⁺ biosynthesis and photoreceptor survival. Biallelic variants in NMNAT1 have been implicated in autosomal recessive cone-rod dystrophy (CRD), a condition marked by early macular atrophy and progressive loss of cone function (2 probands) (PMID:29184169).

Inheritance is autosomal recessive, with two unrelated individuals reported: Case 1 carried a homozygous missense variant c.271G>A (p.Glu91Lys) (PMID:29184169), and Case 2 was compound heterozygous for c.53A>G (p.Asn18Ser) and c.769G>A (p.Glu257Lys) (PMID:29184169). No additional affected relatives were described, and no segregation data are available.

All three pathogenic changes are missense substitutions affecting conserved residues within the enzymatic domain, with no loss-of-function or splice variants reported in CRD patients. The spectrum includes c.271G>A (p.Glu91Lys), c.53A>G (p.Asn18Ser), and the hypomorphic c.769G>A (p.Glu257Lys), the latter known for reduced penetrance in LCA when homozygous (PMID:24830548).

Functional characterization of NMNAT1 mutants associated with retinal degeneration demonstrates that many missense alleles retain baseline enzymatic activity but lose stability under stress, leading to reduced NAD⁺ synthesis in photoreceptors. Heat-shock assays revealed mutant proteins with accelerated unfolding compared to wild type (PMID:26018082). In a knock-in mouse, the p.Val9Met allele induced retina-specific NAD⁺ depletion and elevated poly(ADP-ribose), culminating in photoreceptor apoptosis (PMID:33709122).

Mouse models carrying patient-derived NMNAT1 mutations recapitulate the human phenotype, exhibiting early photoreceptor loss, optic atrophy, and diminished electroretinogram responses. Gene augmentation via AAV-mediated NMNAT1 delivery rescued retinal structure and function in p.Val9Met mice, underscoring therapeutic potential (PMID:27207593); (PMID:32775493).

Despite limited case numbers, genetic and robust experimental data collectively support a moderate clinical validity for NMNAT1 in cone-rod dystrophy. Further identification of additional families and segregation studies will strengthen this association. Key take-home: NMNAT1 should be included in genetic testing panels for autosomal recessive CRD with macular atrophy.

References

• European journal of human genetics • 2018 • NMNAT1 variants cause cone and cone-rod dystrophy PMID:29184169
• JAMA ophthalmology • 2014 • Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1 PMID:24830548
• The Journal of biological chemistry • 2015 • Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants PMID:26018082
• Human molecular genetics • 2021 • Mutant Nmnat1 leads to a retina-specific decrease of NAD+ accompanied by increased poly(ADP-ribose) in a mouse model of NMNAT1-associated retinal degeneration PMID:33709122
• The American journal of pathology • 2016 • Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease PMID:27207593
• Molecular therapy. Methods & clinical development • 2020 • Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration PMID:32775493

Evidence Based Scoring (AI generated)